Treatment of GIST: Clarifying the Data

Gastrointestinal stromal tumor (GIST), once the bane of sarcoma oncologists, now represents the model solid tumor exemplifying the efficacy of targeted therapies. These mesenchymal tumors that typically arise along the intestinal tract are characterized by their lack of response to standard cytotoxic therapies. Treatment options changed when Hirota and colleagues described the presence of the KIT tyrosine kinase receptor on these tumors. Their discovery that KIT was frequently mutated, leading to constitutive activation of the gene, also transformed our thinking about GIST. In their elegant experiment, when the gene was expressed in a knock-in mouse model, GIST tumors developed.[1] These findings changed our understanding of GIST and led to the development of targeted therapy for these tumors, as reviewed by Stein and colleagues in their paper entitled "New Therapeutic Options in Gastrointestinal Stromal Tumors."

In their introduction, Stein and coauthors assert that the advent of small-molecule tyrosine kinase inhibitors has led to the delay of disease progression and decreased mortality. The majority of trials to date have focused on patients with metastatic disease, and clearly, kinase inhibitors have altered the natural history of metastatic GIST. Response for patients treated with imatinib mesylate (Gleevec), the first agent approved for therapy of GIST, range from 52% to 88%.[2-4] This is in marked contrast to the 10% response rate for cytotoxic therapy.[5]

High-Dose vs Low-Dose Therapy

In their discussion of the studies evaluating the safety and efficacy of high-dose imatinib (400 mg twice daily), the authors focus on the data from the phase III randomized European Organisation for Research and Treatment of Cancer (EORTC) study of low-dose (400 mg daily) vs high-dose therapy,[4] rather than the phase II trial led by the EORTC sarcoma group.[6] This phase II trial supported the tolerability and efficacy of high-dose imatinib in GIST, as had been suggested by phase I data.[3] The authors correctly point out that the EORTC phase III data did not demonstrate a difference in overall survival (OS) but did find greater toxicity in the high-dose arm.

However, they do not discuss the differences in the progression-free survival (PFS) benefit noted in the EORTC-led study compared to the US Intergroup trial.[7] The two studies were designed with different endpoints: PFS for the former and OS for the latter. Thus, the EORTC trial enrolled a greater number of patients. The smaller number of patients in the US Intergroup trial may not have allowed this difference to be observed. Some of the improvement in PFS is accounted for by the benefit that patients with exon 9 mutations obtained from high-dose therapy, despite the small number of these patients.[8] The EORTC study also found that both PFS and OS were greater in imatinib-treated patients with wild-type tumors than in those with exon 9 mutations. This was the opposite of the findings reported in the US-Finland study.[9]

The Meta-GIST analysis, utilizing the combined data sets from both phase III trials, confirmed the PFS benefit of higher-dose therapy, particularly for those with exon 9 mutations.[10] This finding supports the current guidelines as highlighted by the authors.

Adjuvant Imatinib

The testing of imatinib in adjuvant therapy has been led by the American College of Surgeons Oncology Group. Z9000 was a phase II trial of low-dose imatinib in patients with resected GIST at high risk for disease recurrence by virtue of a large primary tumor, tumor rupture, or evidence of limited peritoneal metastases. The authors report correctly that imatinib was found to be safe in this patient population, but disease outcome with therapy has not been reported at this time.

The randomized Z9001 trial of adjuvant imatinib vs placebo following complete surgical resection of primary GIST greater than 3 cm demonstrated an improved PFS for patients receiving adjuvant imatinib, with no difference in OS between these two patient groups.[11] This difference, however, appeared to be most significant in patients with tumors greater than 10 cm (hazard ratio [HR] = 0.19, P < .001), less so for those with tumors measuring 6 to 10 cm (HR = 0.37, P = .01), but not significant in those with the smallest tumors, 3 to 6 cm, (HR = 0.44, P = .15).[11]

Additional studies being conducted in Europe will help our understanding of the role of adjuvant imatinib. The Scandinavian Sarcoma Group is randomizing patients at high risk of recurrence to low-dose imatinib for 12 vs 36 months, and in this same population, the EORTC is testing low-dose imatinib vs placebo for 24 months. The latter study stands out as the only trial whose primary endpoint is overall survival rather than progression-free survival. To date, the data on adjuvant therapy have not demonstrated that we are curing more patients-ie, we have not altered the mortality associated with this disease.

Sunitinib

Based on phase I to III testing, sunitinib malate (Sutent) is now a standard second-line agent for patients with metastatic GIST who have progressed on or who are intolerant to imatinib. Response rates from the early testing of sunitinib were confirmed in the phase III trial. Although the median PFS was 27.3 weeks for the entire population of patients on sunitinib, some tumors have mutations that clearly are more responsive to sunitinib-for example, wild-type tumors, KIT exon 9 tumors, and tumors with KIT exon 11 mutations that have acquired secondary mutations in the ATP-binding pocket of KIT, but not those with KIT exon 17 or platelet-derived growth factor receptor (PDGFR) exon 18 mutations.[12]

More recently, investigators reported a phase II study of sunitinib at 37.5 mg/d rather than 50 mg/d for 4 weeks followed by a 2-week break. This study showed that the daily regimen has activity and is tolerated without an apparent increase in toxicity.[13] This schedule theoretically has advantages, as it eliminates the 2-week break of the standard regimen, which leaves tumors without kinase inhibition.

Other Agents

Additional therapeutic options are being evaluated in this setting. As discussed by Stein and coauthors, nilotinib (Tasigna) has been tested as a single agent as well as in combination with imatinib. Rash and hyperbilirubinemia were the two dose-limiting side effects when nilotinib was used in combination with imatinib.[14]

Masatinib is a novel tyrosine kinase inhibitor with enhanced in vitro activity against mutations that are less responsive to imatinib. The current role for this drug is unknown. As Stein and colleagues correctly point out, IPI-504 has the most distinctive mechanism of action in treating GIST. In vitro data suggest this agent may be especially effective in tumors with complex kinase mutations, as seen in tumors that have progressed on imatinib.[15] The optimal dose and schedule of IPI-504 are still undergoing phase I testing.

Conclusions

Stein and colleagues' paper covers the salient points about GIST management. The data from the studies they discuss are complex, and in my discussion, I have included additional information on study design and trial details that aid in the understanding of the study results. The data clearly support the conclusion that targeted therapy has delayed disease progression, but we do not have data demonstrating that we are affecting associated mortality. Newer therapies and approaches continue to be studied, and indeed, this is not the end of the GIST story.

-Margaret von Mehren, MD

Financial Disclosure:Dr. von Mehren is a consultant for Novartis, Pfizer, and Medimmune. She also has received research support from Novartis.

References:

1. Hirota S, Isozaki K, Moriyama Y, et al: Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577-580, 1998.

2. Demetri G, von Mehren M, Blanke C, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480, 2002.

3. van Oosterom A, Judson I, Verweij J, et al: Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: A phase I study. Lancet 358:1421-1423, 2001.

4. Verweij J, Casali PG, Zalcberg J, et al: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 364:1127-1134, 2004.

5. Dematteo RP, Heinrich MC, El-Rifai WM, et al: Clinical management of gastrointestinal stromal tumors: Before and after STI-571. Hum Pathol 33:466-477, 2002.

6. Verweij J, Von Oosterom A, Blay J, et al: Imatinib mesylate is an active agent for GIST but does not yield responses in other soft tissue sarcomas that are unselected for a molecular target. Eur J Cancer 39:2006-2011, 2003.

7. Rankin C, von Mehren M, Blanke C, et al: Dose effect of imatinib (IM) in patients (pts) with metastatic GIST-Phase III Sarcoma Group Study S0033 (abstract 9005). Proc Am Soc Clin Oncol 23:815, 2004.

8. Debiec-Rychter M, Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093-1103, 2006.

9. Heinrich M, Corless C, Demetri G, et al: Kinase mutations and imatinib mesylate response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349, 2003.

10. Van Glabbeke mm, Owzar K, Rankin C, et al: Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): A meta-analysis based on 1,640 patients (pts) (abstract 10004). J Clin Oncol 25(18S):546s, 2007.

11. DeMatteo R, Owzar K, Maki R, et al: Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Intergroup phase III trial ACOSOG Z9001 (abstract 10079). Presented at the American Society of Clinical Oncology Annual Meeting, Chicago, June 1–5, 2007.

12. Corless CL, Heinrich MC: Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol October 16, 2007 [epub ahead of print].

13. George S, Blay JY, Casali PG, et al: Continuous daily dosing (CDD) of sunitinib malate (SU) compares favorably with intermittent dosing in pts with advanced GIST (abstract 10015). J Clin Oncol 25(18S):548s, 2007.

14. von Mehren M, Reichardt P, Casali PG, et al: A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (abstract 10023). J Clin Oncol 25(18S):550s, 2007.

15. Demetri GD, George S, Morgan JA, et al: Inhibition of the heat shock protein 90 (Hsp90) chaperone with the novel agent IPI-504 to overcome resistance to tyrosine kinase inhibitors (TKIs) in metastatic GIST: Updated results of a phase I trial (abstract 10024). J Clin Oncol 25(18S):551s, 2007.